NM_001259.8:c.915G>T

CDK6 · NP_001250.1:p.(Arg305Ser) · NM_001259.8

GRCh37: chr7:92244520 C>A · GRCh38: chr7:92615206 C>A

Gene: CDK6 Transcript: NM_001259.8

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

CDK6

Transcript

NM_001259.8

Protein

NP_001250.1:p.(Arg305Ser)

gnomAD AF

2.4781489218813115e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001259.8:c.915G>T (p.Arg305Ser) in CDK6 is a missense variant observed at extremely low frequency in population databases (gnomAD v2.1 AF=0.0016%, v4.1 AF=0.00025%), meeting PM2 at supporting level.

Multiple in silico tools predict a benign effect: REVEL score 0.126, BayesDel score -0.39903, and SpliceAI max delta 0.02. These concordant predictions meet BP4 at supporting benign level.

The variant is absent from ClinVar, COSMIC, and the published literature. No functional, segregation, or case-control data are available. No pathogenic comparator exists at residue Arg305.

With one supporting criterion for pathogenicity (PM2) and one supporting benign criterion (BP4), the evidence is conflicting and insufficient to classify this variant as either pathogenic or benign. The variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant (p.Arg305Ser); it does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). Per ClinGen SVI PVS1 recommendations (PMC6185798), PVS1 is not applicable to missense substitutions.	pvs1_generic_framework
PS1	Not met	No previously established pathogenic missense variant at the same amino acid residue (Arg305) has been identified in ClinVar or the published literature. There is no basis to apply PS1.	clinvar
PS2	Not met	No de novo occurrence data with confirmed paternity and maternity are available for this variant.
PS3	Not met	No well-established in vitro or in vivo functional studies have been reported for this variant. OncoKB classifies it as Unknown Oncogenic Effect with no variant-specific functional evidence.	oncokb
PS4	Not met	No case-control or cohort data demonstrate a significantly increased prevalence of this variant in affected individuals compared to controls.
PS5	Not met	This variant does not lie in a statistically significant mutational hotspot, and no established pathogenic variant shares the same amino acid change (see PS1). The residue is not in a well-characterized functional domain with prior pathogenic variation.
PM1	Not met	Residue Arg305 in CDK6 is not located in a statistically significant mutational hotspot, nor is it in a well-established critical functional domain lacking benign variation. The hotspot screen is negative.
PM2	Met	This variant is extremely rare in population databases. In gnomAD v2.1 it is observed at an allele frequency of 0.0016% (4/249,266 alleles, no homozygotes; grpmax FAF 4.41e-05). In gnomAD v4.1 it is observed at 0.00025% (4/1,614,108 alleles). It is absent from gnomAD-Canada. These frequencies are well below the PM2 threshold of 0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant has been reported at the same amino acid residue (Arg305) in CDK6. The automated PM5 candidate search found zero same-residue comparator variants in ClinVar.	pm5_candidates
PM6	Not met	No de novo occurrence data (assumed or confirmed) are available for this variant.
PP1	Not met	No co-segregation data in affected family members are available for this variant.
PP2	Not met	CDK6 does not have an established gene-level constraint profile showing a low rate of benign missense variation in a germline disease context. The HCI prior is unavailable for CDK6, and no ClinGen-curated missense constraint data exist.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.126 (well below the 0.5 pathogenic threshold), BayesDel score is -0.39903 (predicting benign), and SpliceAI predicts no splicing impact (max delta 0.02). These do not meet the threshold for PP3.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data are available to assess specificity for a CDK6-associated disorder.
PP5	Not met	No reputable source (ClinVar, clinical laboratory, or published report) has classified this variant as pathogenic.	clinvar
BA1	Not met	The allele frequency in gnomAD (0.0016% in v2.1, 0.00025% in v4.1) is far below the BA1 threshold of 1%.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency in gnomAD (0.0016% in v2.1, 0.00025% in v4.1) is far below the BS1 threshold of 0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No data available on observation of this variant in healthy adults where full penetrance of a CDK6-associated disorder would be expected at an early age.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate that this variant has no deleterious effect on protein function.	oncokb
BS4	Not met	No segregation data in affected families are available to assess lack of co-segregation with disease.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. CDK6 lacks a well-established germline disease association limited to truncating variants; the available literature does not demonstrate that CDK6 germline disease is caused exclusively or primarily by loss-of-function truncations.
BP2	Not met	BP2 applies to missense variants in genes where only missense variants cause disease. CDK6 does not meet this criterion; loss-of-function mechanism is also supported.
BP3	N/A	This is a missense substitution, not an in-frame deletion or insertion in a repetitive region.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.126 (below pathogenic threshold), BayesDel score is -0.39903 (strongly predicting benign), and SpliceAI predicts no splicing alteration (max delta 0.02). Three independent in silico tools are concordant in predicting a benign or non-damaging effect.	revel bayesdel spliceai
BP5	Not met	No case has been reported in which this variant is observed in an individual with an alternate molecular basis for disease.
BP6	Not met	No reputable source (ClinVar, clinical laboratory) has classified this variant as benign.	clinvar
BP7	N/A	This is a missense variant (p.Arg305Ser), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
PM3	N/A	CDK6 is not established as a recessive disease gene. No data for this variant detected in trans with a pathogenic variant.
PM4	N/A	This is a missense substitution, not a non-repeat in-frame deletion/insertion or stop-loss variant.

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